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Levodopa (SINEMET)

SINEMET® (carbidopa levodopa) is a combination of carbidopa
and levodopa for the treatment of Parkinson's disease and syndrome.

Carbidopa, an inhibitor of aromatic amino acid decarboxylation,
is a white, crystalline compound, slightly soluble in water, with a molecular
weight of 244.3. It is designated chemically as (-)-L-α-
hydrazino-α-methyl-β-(3,4-dihydroxybenzene) propanoic acid monohydrate. Its
empirical formula is C10H14N2O4•H2O,
and its structural formula is:

Tablet content is expressed in terms of anhydrous carbidopa
which has a molecular weight of 226.3.

Levodopa, an aromatic amino acid, is a white, crystalline
compound, slightly soluble in water, with a molecular weight of 197.2. It is
designated chemically as (â€”)-L-α-amino-β-(3,4-dihydroxybenzene) propanoic
acid. Its empirical formula is C9H11NO4, and its
structural formula is:

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Striatal dopamine levels in symptomatic Parkinson's disease
are decreased by 60 to 80%, striatal dopaminergic neurotransmission may be
enhanced by exogenous supplementation of dopamine through administration of
dopamine's precursor, levodopa. A small percentage of each levodopa dose
crosses the blood-brain barrier and is decarboxylated to dopamine. This newly
formed dopamine then is available to stimulate dopaminergic receptors, thus
compensating for the depleted supply of endogenous dopamine.

L-DOPA crosses the protective blood–brain barrier,
whereas dopamine itself cannot. Thus, L-DOPA is used to
increase dopamine concentrations in the treatment of Parkinson's
disease and dopamine-responsive dystonia. This treatment was made
practical and proven clinically by George Cotzias and his coworkers,
for which they won the 1969 Lasker Prize. Once L-DOPA has
entered the central nervous system, it is converted into dopamine by
the enzyme aromatic L-amino acid decarboxylase, also known
as DOPA decarboxylase. Pyridoxal phosphate (vitamin B6)
is a required cofactor in this reaction, and may occasionally be
administered along with L-DOPA, usually in the form of pyridoxine.

Besides the central nervous system, L-DOPA is also
converted into dopamine from within the peripheral nervous system.
Excessive peripheral dopamine signaling causes many of the adverse side
effects seen with sole L-DOPA administration. To bypass these
effects, it is standard clinical practice to coadminister (with L-DOPA) a
peripheral DOPA decarboxylase inhibitor (DDCI) such as carbidopa(medicines
containing carbidopa, either alone or in combination with L-DOPA, are
branded as Lodosyn (Aton Pharma) Sinemet(Merck Sharp & Dohme
Limited), Pharmacopa (Jazz Pharmaceuticals), Atamet (UCB), and Stalevo (Orion
Corporation) or with a benserazide (combination medicines are branded
Madopar or Prolopa), to prevent the peripheral synthesis of dopamine from L-DOPA.
Coadministration of pyridoxine without a DDCI accelerates the
peripheral decarboxylation of L-DOPA to such an extent that it negates
the effects of L-DOPA administration, a phenomenon that historically
caused great confusion.

In addition, L-DOPA, co-administered with a peripheral
DDCI, has been investigated as a potential treatment for restless leg
syndrome. However, studies have demonstrated "no clear picture
of reduced symptoms".

The two types of response seen with administration of L-DOPA
are:

The
short-duration response is related to the half-life of the drug.

The
longer-duration response depends on the accumulation of effects over at
least two weeks, during which ΔFosB accumulates in nigrostriatal
neurons. In the treatment of Parkinson's disease, this response is evident
only in early therapy, as the inability of the brain to store dopamine is
not yet a concern.

Psychotic episodes including delusions, hallucinations, and
paranoid ideation, bradykinetic episodes (“on-off” phenomenon),
confusion, agitation, dizziness, somnolence, dream abnormalities including
nightmares, insomnia, paresthesia, headache, depression with or without
development of suicidal tendencies, dementia, pathological gambling,
increased libido including hypersexuality, impulse control symptoms.
Convulsions also have occurred; however, a causal relationship with SINEMET has
not been established.

The optimum daily dosage of SINEMET must be determined by
careful titration in each patient. SINEMET tablets are available in a 1:4 ratio
of carbidopa to levodopa (SINEMET 25-100) as well as 1:10 ratio (SINEMET 25-250
and SINEMET 10-100). Tablets of the two ratios may be given separately or
combined as needed to provide the optimum dosage.

Studies show that peripheral dopa decarboxylase is
saturated by carbidopa at approximately 70 to 100 mg a day. Patients receiving
less than this amount of carbidopa are more likely to experience nausea and
vomiting.

Usual Initial Dosage

Dosage is best initiated with one tablet of SINEMET 25-100
three times a day. This dosage schedule provides 75 mg of carbidopa per day.
Dosage may be increased by one tablet every day or every other day, as
necessary, until a dosage of eight tablets of SINEMET 25-100 a day is reached.

If SINEMET 10-100 is used, dosage may be initiated with one
tablet three or four times a day. However, this will not provide an adequate
amount of carbidopa for many patients. Dosage may be increased by one tablet
every day or every other day until a total of eight tablets (2 tablets q.i.d.)
is reached.

How To Transfer
Patients From Levodopa

Levodopa must be discontinued at least twelve hours before
starting SINEMET. A daily dosage of SINEMET should be chosen that will
provide approximately 25% of the previous levodopa dosage. Patients who are
taking less than 1500 mg of levodopa a day should be started on one tablet of
SINEMET 25-100 three or four times a day. The suggested starting dosage for
most patients taking more than 1500 mg of levodopa is one tablet of SINEMET
25-250 three or four times a day.

Maintenance

Therapy should be individualized and adjusted according to
the desired therapeutic response. At least 70 to 100 mg of carbidopa per day
should be provided. When a greater proportion of carbidopa is required, one
tablet of SINEMET 25-100 may be substituted for each tablet of SINEMET 10-100.
When more levodopa is required, SINEMET 25-250 should be substituted for
SINEMET 25-100 or SINEMET 10-100. If necessary, the dosage of carbidopa
levodopa 25-250 may be increased by onehalf or one tablet every day or every
other day to a maximum of eight tablets a day. Experience with total daily
dosages of carbidopa greater than 200 mg is limited.

Because both therapeutic and adverse responses occur more
rapidly with SINEMET than with levodopa alone, patients should be monitored
closely during the dose adjustment period. Specifically, involuntary movements
will occur more rapidly with SINEMET than with levodopa. The occurrence of
involuntary movements may require dosage reduction. Blepharospasm may
be a useful early sign of excess dosage in some patients.

Addition Of Other
Antiparkinsonian Medications

Standard drugs for Parkinson's disease, other than levodopa
without a decarboxylase inhibitor, may be used concomitantly while SINEMET is
being administered, although dosage adjustments may be required.

Interruption Of
Therapy

Sporadic cases of hyperpyrexia and confusion have been
associated with dose reductions and withdrawal of SINEMET. Patients should be
observed carefully if abrupt reduction or discontinuation of SINEMET is
required, especially if the patient is receiving neuroleptics.

If general anesthesia is required, SINEMET may be
continued as long as the patient is permitted to take fluids and medication by
mouth. If therapy is interrupted temporarily, the patient should be observed
for symptoms resembling NMS, and the usual daily dosage may be administered as
soon as the patient is able to take oral medication.

Caution should be exercised when the following drugs are
administered concomitantly with SINEMET.

Symptomatic postural hypotension occurred when
SINEMET was added to the treatment of a patient receiving antihypertensive drugs.
Therefore, when therapy with SINEMET is started, dosage adjustment of the
antihypertensive drug may be required.

For patients receiving MAO inhibitors (Type A or B).
Concomitant therapy with selegiline and carbidopa levodopa may be
associated with severe orthostatic hypotension not attributable to carbidopa
levodopa alone

There have been rare reports of adverse reactions, including
hypertension and dyskinesia, resulting from the concomitant use of
tricyclic antidepressants and SINEMET.

Dopamine D2 receptor antagonists (e.g., phenothiazines,
butyrophenones, risperidone) and isoniazid may reduce the therapeutic
effects of levodopa. In addition, the beneficial effects of levodopa in Parkinson's
disease have been reported to be reversed by phenytoin and
papaverine. Patients taking these drugs with SINEMET should be carefully
observed for loss of therapeutic response.

Use of SINEMET with dopamine-depleting agents (e.g.,
reserpine and tetrabenazine) or other drugs known to deplete monoamine stores
is not recommended.

SINEMET and iron salts or multivitamins containing iron
salts should be coadministered with caution. Iron salts can form chelates with
levodopa and carbidopa and consequently reduce the bioavailability of carbidopa
and levodopa.

Although metoclopramide may increase the
bioavailability of levodopa by increasing gastric emptying, metoclopramide
may also adversely affect disease control by its dopamine receptor antagonistic
properties.

When SINEMET is to be given to patients who are being
treated with levodopa, levodopa must be discontinued at least twelve hours
before therapy with SINEMET is started. In order to reduce adverse reactions,
it is necessary to individualize therapy.

The addition of carbidopa with levodopa in the form of
SINEMET reduces the peripheral effects (nausea, vomiting) due to
decarboxylation of levodopa; however, carbidopa does not decrease the adverse
reactions due to the central effects of levodopa. Because carbidopa permits
more levodopa to reach the brain and more dopamine to be formed,
certain adverse central nervous system (CNS) effects, e.g.,
dyskinesias (involuntary movements), may occur at lower dosages and sooner with
SINEMET than with levodopa alone.

All patients should be observed carefully for the
development of depression with concomitant suicidal tendencies.

SINEMET should be administered cautiously to patients with
severe cardiovascular or pulmonary disease, bronchial asthma,
renal, hepatic or endocrine disease.

As with levodopa, care should be exercised in administering
SINEMET to patients with a history of myocardial infarction who
have residual atrial, nodal, or ventricular arrhythmias. In such
patients, cardiac function should be monitored with particular care during the
period of initial dosage adjustment, in a facility with provisions for
intensive cardiac care.

As with levodopa, treatment with SINEMET may increase the
possibility of upper gastrointestinal hemorrhage in patients
with a history of peptic ulcer.

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